S156: INTERNATIONAL, PROSPECTIVE STUDY COMPARING NILOTINIB VERSUS IMATINIB WITH EARLY SWITCH TO NILOTINIB TO OBTAIN SUSTAINED TREATMENT-FREE REMISSION IN PATIENTS WITH WITH CHRONIC MYELOID LEUKEMIA
Authors: F. Pane, F. Castagnetti, L. Luciano, A. Russo Rossi, E. Abruzzese, R. Bassan, G. Binotto, G. Caocci, G. Cimino, P. Fazi, A. Gozzini, M. Lunghi, R. Marasca, B. Martino, M. Bonifacio, F. Cavazzini, F. Paoloni, G. Saglio, S. Sica, A. Tafuri, D. Vallisa, M. Vignetti, P. Westerweel, G. Rosti, M. Breccia
Journal: HemaSphere (2022)

Background: Treatment free remission (TFR) is one of the most important goals of the CML treatment but, so far, the best treatment to reach this aim is still undefined. It is widely accepted that a sustained deep molecular remission (DMR) is the pre-requisite to discontinue TKI, and it is expected that in patients who start treatment with imatinib (IMA) and fail early molecular remission (EMR), a switch to a second generation TKI may improve the probability of achieving a DMR Aims: We launched in November 2016 an international, prospective, interventional, randomized, two arms, study to evaluate both the depth of the molecular response and the rate of TFR in newly diagnosed CP-CML patients treated with a second generation TKI (Nilotinib, NIL) or with IMA followed by switching to NIL in absence of optimal response (defined according the ELN 2013 criteria (Clinical Trial number 02602314). Methods: The patients are randomized 1:1 between NIL and IM according to Sokal risk score (high versus intermediate/low risk) and country. All the patients who obtain a residual disease reduction greater than 4.0 logs (MR4.0) within the first three years of treatment and maintain this level of response up to the end of the fourth years of therapy qualify for the discontinuation phase of the study. The study has two primary end-points: a) the rates of molecular response (MR4.5) at 24 months, and b) the rate of patients who remain in sustained treatment free remission (≥MR3.0) without molecular relapse 12 months after entering the TFR phase. The molecular relapse is defined as loss of MMR or confirmed loss of MR3.0 (figure). Results: From November 2016 to January 2021, 457 patients with newly diagnosed CP-CML patients were enrolled into the study and 448 of these (228 and 220 randomized to the NIL and IMA arms, respectively) were evaluable (mean age 54.2 yrs - range 19.4 – 85.8). At baseline, 183 (40.8%), 191 (42.6%) and 72 (16.1%) patients were classified as low, intermediate, or high-risk Sokal, respectively, while 278 (62.3%), 128 (28.7%) and 40 (9.0%) had a low, intermediate, or high-risk ELTS risk score. The median follow-up of the whole cohort of patients is 30.4 mo. Fifthy-six (25.4%) of the 220 patients of the IMA arm did not fulfill the ELN criteria for optimal response within the first 12 mo. of treatment and, according to the protocol, switched to NIL therapy. At the last analysis of the protocol database (February 2022), 59 patients had had stopped the protocol treatment since their decision, death (24), toxicity (23), progression (9), uncontrolled second neoplasia (2) or protocol violation (1), 69 patients had not reach 24 mo. of follow-up and other 15 had missing data. Of the remaining 304 patients, 35 showed non optimal response to therapy. At the 24 mo. of follow-up, 76 of the 322 patients with an available molecular response (23.6%), reached a MR4.5 response that showed a significantly higher frequency within the patients randomized to the NIL arm (48 vs 28; p=0.015) (first primary co-endpoint of the study). Image:Summary/Conclusion: This is the first and, so far, the unique prospective study comparing not only the rate of DMR but, more important, also the rate of TFR according to treatment: a second generation TKI frontline vs IMA frontline followed by the same second generation in case of non-optimal response. The analysis of the first co-primary endpoint indicates that, despite the early switch in the IMA randomized patients, NIL therapy is more effective to induce DMR. Subsequent analysis will clarify whether the higher rates of DMR in the NIL arm may translate into a higher rate of TFR.